Limited availability of insulin producing tissue, requires optimization of outcomes in islet processing and pretransplant culture, while minimizing islet loss in the early post-transplant period, as well as long-term. The Clinical Component of this proposal will focus on treating islets pre-transplant, and recipients (during and post-transplant), with selected agents with a unique spectrum of anti-inflammatory, anti-apoptotic and beta cell enhancing properties (Lisofylline and Exenatide), to improve beta cell function and viability, maximizing pre-transplant functional islet mass, islet engraftment and long-term function, in patients with Type 1 diabetes. The two treatment variables, Lisofylline and Exenatide (and their effect on engraftment and beta cell function) will be tested in a factorial design with a balanced randomization scheme into the four treatment groups. The randomization will be performed centrally and will be stratified by center. All Islets will be processed at the University of Miami, and recipients (N=96) will be recruited and transplanted at 3 sites (UM, Baylor-Houston and UVA). The Mechanistic Component of this proposal will enable us to identify those preparations that have optimal beta cell content, viability and potency. Determination of beta cell viability, analysis of mitochondrial potential and apoptotic status and dynamic measures of GSIS will allow to establish not only islet integrity prior to transplantation, but also comparability of the islet preparation used in the selected treatment groups. Measures of nonspecific inflammation in the early post transplant period will determine the most effective treatment strategy to maximize engraftment. Studies of recipient immune status, including measures of auto and allo reactivity, as well as the ability of cells to respond to nonspecific stimuli in the setting of global immune suppression, will assess whether or not immune mediated islet loss is decreased in recipients of Lisofylline and/or Exenatide, and to identify indicators of long-term islet graft acceptance.